Methods for the preparation of 4-hydroxy benzothiophene

ABSTRACT

The present invention is concerned with a novel process for the preparation of the hydroxybenzothiophene of formula I  
                 
 
     comprising cyclocarbonylation of a compound of formula II  
                 
 
     wherein Y is as defined in the specification, followed by saponification. The compound of Formula I is a building block of pharmaceutically active substances, e.g. 5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-7-benzothiophenylmethyl]-2,4-thiazolidinedione and the corresponding sodium salt which are from agents useful in the treatment of diabetes.

BACKGROUND OF THE INVENTION

[0001] Methods for the preparation of 4-hydroxybenzothiophene have beendescribed by Iwasaki et al. (1991) J. Org. Chem. 1991. 56, 1922. Here acyclocarbonylation of a primary allylacetate is performed in presence ofa high catalyst loading. Further, this process is characterized by atleast five process steps which in part require extreme reactionconditions. Therefore, a simpler more efficient process utilizing lessprocess steps has been long desired.

SUMMARY OF INVENTION

[0002] The present invention is concerned with a novel process for thepreparation of benzothiophene derivatives, especially with thepreparation of 4-hydroxybenzothiophene. 4-Hydroxybenzothiophene is abuilding block for pharmaceutically active compounds, e.g.5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-7-benzothiophenylmethyl]-2,4-thiazolidinedione.This compound is known in the art and is described for example inInternational Patent Application WO 94/27995. It is especially usefulfor prophylaxis and treatment of diabetes mellitus type I and II.

[0003] Surprisingly it has been found that using the process accordingto the present invention 4-hydroxybenzothiophene can be prepared withless process steps under moderate conditions with an outstanding yield.

DETAILED DESCRIPTION

[0004] In accordance with this invention, a new procedure is providedfor preparing 4-hydroxybenzothiophene having the formula

[0005] from a compound of

[0006] wherein Y is halogen or —OR; and

[0007] —OR is an aryloxy group or a group of formulae —O—(CO)—R′,—O—(CO)—O—R″, or —O—(PO)—(OR″)₂, wherein R′ is alkyl,perfluoro-C₁₋₂₀-alkyl, aryl, R″ is alkyl, aryl or benzyl;

[0008] which comprises cyclocarbonylating the compound of formula II byreacting, in an organic solvent medium containing a carboxylic acidanhydride and a base, the compound of formula II with carbon monoxide inthe presence of a carbonylation catalyst capable of complexing withcarbon monoxide to produce the carboxylic acid ester of the compound offormula I as a reaction product and thereafter saponifying this reactionproduct to produce the compound of formula I above.

[0009] The cyclocarbonylation is carried out by introducing carbonmonoxide into the reaction medium containing the compound of formula IIabove and a carbonylation catalyst capable of complexing with carbonmonoxide to produce the carboxylic acid ester of the compound of formulaI as a reaction product. The saponification step is carried out afterthis reaction product is formed. The saponification is carried out byadding a base to the reaction medium so that the pH is raised to anyvalue of from 8 to 14.

[0010] Surprisingly, it has been found that using the process of thisinvention, the 4-hydroxybenzothiophene can be prepared with less processsteps under moderate conditions and with an outstanding yield. Theprocess also provides an efficient cyclocarbonylation reaction undermild conditions in a single reaction medium so that the startingmaterial for this reaction, i.e., the compound of formula II, does nothave to be purified such as by distillation but can be used as crudematerial. Therefore, this process provides an efficientcyclocarbonylation reaction under mild conditions. In addition,substrates for the cyclocarbonylation reaction (compound of Formula II)do not need to be purified, e.g. by distillation, but can be used as“crude” material.

[0011] According to the present invention, the term“ccyclocarbonylation” refers to an introduction of a carbonyl group bymeans of carbon monoxide gas coupled with the formation of a cyclic ringstructure.

[0012] The term “saponification” refers to the hydrolysis of an esterunder basic conditions.

[0013] The term “transition metal compound” refers to a metal-phosphinecomplex compound wherein the term metal refers to Pd, Pt, Ru, Co, Rh orNi, preferably Pd.

[0014] The term “ligand” refers to phosphine, arsine or stibinederivatives, preferable phosphine derivatives, of general formulaeP(R¹)(R²)(R³), (R¹)(R²)P—(X)—P(R¹)(R²), As(R¹)(R²)(R³) orSb(R¹)(R²)(R³), preferably P(R¹)(R²)(R³), wherein R¹, R², and R³ aredefined below.

[0015] The term “alkyl” refers to a branched or straight chainmonovalent alkyl radical of one to nine carbon atoms (unless otherwiseindicated), preferably one to four (lower) carbon atoms. This term isfurther exemplified by such radicals as methyl, ethyl, n-propyl,isopropyl, i-butyl, n-butyl, t-butyl and the like.

[0016] The term “aryl” refers to a monovalent carbocyclic aromaticradical, e.g. phenyl, optionally substituted, independently, withhalogen, lower-alkyl, lower-alkoxy, lower-alkylenedioxy, carboxy,trifluoromethyl and the like, with phenyl being especially preferred.

[0017] The term “lower alkanoic acid” refers to those lower alkanoicacids containing from 2 to 6 carbon acids such as propionic acid, aceticacid, etc.

[0018] The term “aryloxy”, signifies a group of the formula aryl-O— inwhich the term “aryl” has the significance given above. Phenyloxy is apreferred example of such an aryloxy group.

[0019] The term “alkoxy”, alone or in combination, signifies a group ofthe formula alkyl-O— in which the term “alkyl” has the significancegiven above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec.butoxy and tert.butoxy, preferably methoxy and ethoxy.

[0020] The term “alkylenedioxy” refers to C₁₋₃-alkyl-dioxy groups, suchas methylenedioxy, ethylenedioxy or propylenedioxy.

[0021] The term “halogen” refers to fluorine, chlorine, and bromine.

[0022] In more detail, the present invention refers to a process for thepreparation of compounds of formula I

[0023] comprising cyclocarbonylation of a compound of formula II

[0024] wherein Y is halogen or —OR;

[0025] —OR is an aryloxy group or a group of formulae —O—(CO)—R′,—O—(CO)—O—R″ or —O—(PO)—(OR″)₂, wherein R′ is alkyl,perfluoro-C₁₋₂₀-alkyl, aryl, R″ is alkyl, aryl or benzyl;

[0026] followed by saponification.

[0027] In a preferred embodiment of the invention, thecyclocarbonylation reaction is carried out in the presence of a base andthe carbonylation catalyst is a complex of a transition metal compoundwith a ligand.

[0028] In a preferred embodiment of this invention, thecyclocarbonylation reaction carried out in the presence of a base and acarboxylic acid anhydride, one utilizes a catalyst which is a transitionmetal compound complexed with a ligand. Cyclocarbonylation reactions andtheir conditions are known. Any of the conventional conditions utilizedin such cyclocarbonylation reactions can be utilized in accordance withthe process of this invention.

[0029] In accordance with the process of this invention, thiscyclocarbonylation reaction is carried out in the presence of acarbonylation catalyst capable of complexing with carbon monoxide. Anyconventional carbonylation catalyst capable of complexing with carbonmonoxide can be utilized in accordance with this invention. Among thepreferred catalysts are those catalysts which are transition metalcompounds complexed with a ligand. Transition metal compounds useful forthe process of the present invention comprise salts of Pd, Pt, Ru, Co,Rh— or Ni and also include transition metals on an inert support such asPd/C. The use of transition metal compounds as catalysts has beendescribed for example in Matsuzaka et al. (1988) J. Org. Chem. 53, 3832.Preferred transition metal compounds are salts of palladium, e.g.Pd(OAc)₂, Pd₂dba₃, PdCl₂, Pd₂Cl₂(π-allyl)₂, PdCl₂(NCMe)₂,[Pd(NCMe)₄](BF₄)₂, and most preferably Pd(OAc)₂. The mentioned catalystsare known in the art (e.g. U.S. Pat. No. 5,380,861; “Carbonylation,Direct Synthesis of Carbonyl Compounds”, H. M. Colquhoun, D. J.Thompson, M. V. Trigg, Plenum Press, 1991) and/or are commerciallyavailable (e.g. from Fluka, Buchs, Switzerland or Strem Chemicals, Kehl,Germany).

[0030] The ligand of the transition metal compound in the catalyst maybe selected from a group consisting of phosphine, arsine or stibinederivatives, preferable phosphine derivatives of general formulaeP(R¹)(R²)(R³), (R¹)(R²)P—(X)—P(R¹)(R²), As(R¹)(R²)(R³) orSb(R¹)(R²)(R³), preferably P(R¹)(R²)(R³), wherein X, R¹, R², and R³ aredefined below.

[0031] Especially suitable ligands are chiral and non-chiral mono- anddiphosphorus compounds for example described in Houben-Weyl, “Methodender organischen Chemie”, vol. E1, page 106 et seq. Georg Thieme VerlagStuttgart, 1982, and Aspects Homog. Catal., 4, 145-202 (1981),especially those of the formulae

P(R¹)(R²)(R³) and (R¹)(R²)P—(X)—P(R¹)(R²)

[0032] wherein R¹, R² and R³ each independently are C₁₋₈-alkyl,cyclohexyl, benzyl, naphthyl, 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or3-thiophenyl, 2- or 3- or 4-pyridyl, phenyl or phenyl which issubstituted by C₁₋₄-alkyl, C₁₋₄-alkoxy, halogen, trifluoromethyl, loweralkylydenedioxy or phenyl and X is binaphthyl, 6,6′-dimethyl- or6,6′-dimethoxybiphenyl-2,2′-diyl, or one of the groups —(CH₂)_(n)—, —CH₂CH₂—P(C₆H₅)—CH₂CH₂—,

[0033] and n is a number of 1-8.

[0034] Examples of suitable phosphorus ligands are shown in Scheme 1.

[0035] The most preferred phosphorus ligands are triphenylphosphine,

[0036] The preparation of a transition metal complex is explained inmore detail for the corresponding palladium-phosphine complex: Thepalladium-phosphine complex compound is conveniently formed in situ froma palladium component and a phosphine ligand. These palladium componentsis for example metallic palladium, which is optionally supported on acarrier material such as carbon, or a complex or a salt of 0-, 2- or4-valent palladium such as palladium-bis(dibenzylideneacetone),palladium chloride, palladium acetate and the like. For the in situpreparation, the phosphorus ligand/transition metal compound ratio(mol/mol; P/Pd) amounts to about 0.1:1 to 100:1, preferably to about 6:1to 15:1. Suitable phosphine ligands are for example chiral andnon-chiral mono- and diphosphorus compounds such as are described inHouben-Weyl, Methoden der organischen Chemie, volume E1, page 106 et.seq. Georg Thieme Verlag Stuttgart, 1982, and Aspects Homog. Catal., 4,145-202 (1981), especially those described above.

[0037] For the in situ preparation of the palladium-phosphine complexcompound palladium-(II) chloride or palladium-(II) acetate,palladium-dichloro-bis(acetonitrile) and a bis(diphenylphosphino)alkanemay be used.

[0038] Further, the process of the present invention comprises the useof bases for the cyclocarbonylation reaction like tertiary bases such astri-alkyl-amines, di-alkyl-aryl-amines, pyridines, alkyl-N-piperidines,and for example inorganic bases such as NaOH, KOH or salts of carbonicacids. Examples are (alkyl)₃amines, e.g. triethylamine,ethyl-di-isopropyl-amine, pyridine, N-methyl-piperidine, sodium hydrogencarbonate, potassium hydrogen carbonate, di-sodium carbonate, etc. Thepreferred base is triethylamine. However, any base conventionally usedfor cydocarbonylation can be used in the process of this invention.

[0039] Any conventional inert solvent can be used as the reactionmedium. Solvents for the above reaction are known to skilled persons.Preferred solvents are aromatic solvents, e.g. toluene, xylene, benzene,halogenated hydrocarbons, e.g. CH₂Cl₂, nitrites, e.g. acetonitrile,ester, e.g. ethylacetate, amides, e.g. DMF, ether, e.g. THF, dioxane,urethanes, e.g. TMU, sulfoxides, e.g. DMSO, and mixtures thereof. Thepreferred solvent is toluene.

[0040] In carrying out the cyclocarbonylation reaction any of theconditions conventionally employed in carrying out such reaction can beutilized in accordance with this invention. This reaction is carried outso that one mole of carbon monoxide is reacted with one mole of thecompound of formula II to produce the cyclocarbonylated reaction productwhich reaction product is the carboxylic acid ester of the compound offormula I. This reaction is carried out by introducing carbon monoxideinto the reaction medium. In carrying out this reaction, usually astoichiometric excess of carbon monoxide is added to the reaction mediumto ensure complete reaction. This is achieved by adjusting the pressureof the carbon monoxide added. By utilizing the conventional reactionconditions for such cyclocarbonylation reaction, one achieves theformation of the reaction product of one mole of the carbon monoxidewith one mole of the compound of formula II above. The reaction productformed from this reaction is not isolated from the reaction medium butis treated with a base to remove the ester group from the hydroxy moietyon the compound of formula I and form the compound of formula I. In thecyclocarbonylation reaction, the temperature can vary between 40° C. and170° C., preferably between 60-120° C., and most preferably the reactionis performed at about 90° C. The substrate/catalyst ratio (mol/mol;S/Pd) amounts to 1 to 10000, preferably 100 to 5000, more preferably1000 to 2000 and most preferably 1200 to 1500. For the in situpreparation, the above mentioned phosphorus ligand/transition metalcompound ratio (mol/mol; P/Pd) amounts to 0.1:1 to 100:1, preferably 6:1to 15:1. The upper limit for the carbon monoxide (CO) pressure is onlylimited by the specification of the autoclave used. For the lowerpressure limit the carbonylation reaction would work even with a COpressure of 1 bar. Preferably, the CO pressure is about 20 to 70 bar,more preferably 35 to 60 bar.

[0041] The cyclocarbonylation reaction of this invention is carried outin the presence of a base and a carboxylic acid anhydride to form thecarboxylic acid ester of the compound of formula I. Any conventionalcarboxylic acid anhydride can be used, particularly the aroic acidanhydrides and the lower alkanoic acid anhydrides. Among the preferredcarboxylic acid anhydrides are benzoic acid anhydride and acetic acidanhydride with acetic acid anhydride being particularly preferred. Thecarboxylic acid anhydride should be present in the reaction medium insufficient quantity to allow it to react, during the cyclocarbonylationreaction, with all of the compounds of formula II present in thisreaction medium. However, a stoichiometric excess of the carboxylic acidanhydride can be present in the reaction medium.

[0042] Surprisingly it has been found that the “crude” compound ofFormula II can be used for the preparation of the compound of Formula I.A preparation of a crude material is performed by collecting thecompound of Formula II, e.g. 1-(2-thienyl)allyl acetate, with an organicsolvent and drying without further purification. The preparation of thismaterial is exemplified in Example 1. Example 2 B shows the use of thecrude starting material for the preparation of the compound of FormulaI.

[0043] The cyclocarbonylation reaction is followed by saponification.Conditions for saponification reactions are known in the art anddescribed for example in “Practical Organic Chemistry”, A. I. Vogel,Longmans Ed., 1967, p. 390-393. In carrying the saponification reactionof the carboxylation acid ester of formula I, the reaction medium inwhich this reaction product is formed is treated with a base. Anyconventional base can be utilized. Normally, it is preferred to utilizethe alkali metal or alkaline earth metal bases such as alkali metal,hydroxides, alkoxides, etc. In a preferred embodiment of the presentinvention, the saponification is carried out in a biphasic mixture ofaqueous sodium hydroxide and toluene or in an homogeneous mixture ofsodium methylate in methanol.

[0044] Compounds of Formula II maybe prepared by methods known in theart, for example by reaction of a thiophene carbaldehyde of Formula III(illustrated in Scheme 2 a; commercially available, Pluka, Aldrich).

[0045] with a vinyl-metal-X reagent, with -metal-X being —MgCl, —MgBr,—Mgl or —Li, preferably —MgCl or —MgBr, followed by reaction with anacid derivative. Other allyl compounds, e.g. the corresponding allylhalogenides or allyl trialkylammonium salts, are also suitable reagents.The acid derivative can be selected from a group consisting of compoundsof formulae, (R′—CO)₂O, R″O—(CO)—Cl, Cl—(PO)(OR″)₂, R′—(CO)—Hal whereinR′ is alkyl, perfluoro-C₁₋₂₀-alkyl, aryl, R″ is alkyl, aryl or benzyland Hal is Cl or Br. The preferred acid derivative is (R′—CO)₂O, andhere especially the acetanhydride. The most preferred thevinyl-metal-X-reagents are vinylmagnesium chloride or vinylmagnesiumbromide.

[0046] In the most preferred embodiment of the present invention, thecompound of Formula II is prepared by reaction of vinylmagnesiumchloride followed by reaction with acetanhydride as shown in scheme 2,variant a).

[0047] Additional methods for the preparation of compound III aresummarized in scheme 2.

[0048] The compound of Formula I is useful for the preparation ofpharmaceutically active substances, e.g.5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-7-benzothiophenylmethyl]-2,4-thiazolidinedioneand its salts, especially the corresponding sodium salt. A process forthe preparation of this compound has been described for example inInternational Patent Application WO 98/42704.

[0049] In addition, the compounds may be prepared according to thefollowing processes:

[0050] In a first step the compound of Formula I may be converted into4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole byreaction with a mesylate of Formula V

[0051] under basic conditions. The reaction may be performed in solventslike DMF with for example sodium carbonate, potassium carbonate orcesium carbonate, preferably potassium carbonate; or in THF with KtBu;or in toluene and KOH with phase transfer catalysts.

[0052] The above process may be followed by a nitration reaction of4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole to give5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole.Normally nitric acid is used for the nitration reaction which may beperformed at room temperature to about 50° C., preferably roomtemperature.

[0053] The5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleobtained by the above process may be converted into of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleby hydrogenation. The conditions of the hydrogenation reaction (H₂/Raneynickel) are known in the art. Hydrogen pressure may be 1 to 10 bar,preferably 1 bar.

[0054] The above process may be continued by the reaction of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazolewith HHal/NaNO₂ followed by reaction with CH═CHCOOCH₃/CU(I)Hal, whereinHal is Br or Cl, preferably Br. The reaction product in case of Hal isBr ismethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate.

[0055] The reaction ofmethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionatewith thiourea will produce2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one.The reaction is normally performed in alkylalkohols like ethanol.

[0056] This compound(2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one)may then be converted into5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedioneby reaction under acid conditions. The reaction may be performed at 1-4bar, preferably at 1 bar. Acidic conditions are provided by an organicor inorganic acid in an appropriate solvent, e.g. HCl/ethanol.

[0057] The reaction may be optionally continued by conversion of5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedionein a corresponding salt, preferably the sodium salt(5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedione-Na-salt)by reaction under basic conditions, preferably with NaOH in THF.

[0058] A further embodiment of the invention comprises a process for thepreparation of5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedioneand/or of5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedionesodium salt comprising

[0059] a) conversion of a compound of Formula I into4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole byreaction of a compound of Formula I

[0060]  under basic conditions; followed by

[0061] b) nitration of4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole to give5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole;

[0062] c) hydrogenation of5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleto give5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole;followed by

[0063] d) reaction of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazolewith HHal/NaNO₂ and CH═CHCOOCH₃/Cu(I)Hal, wherein Hal is Br or Cl togivemethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate;followed by

[0064] e) reaction ofmethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionatewith thiourea to give2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one;followed by

[0065] f) reaction of2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-oneunder acid conditions to give5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedione;and

[0066] g) optionally followed by reaction of5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedioneunder basic conditions to give5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedione-Na-salt.

[0067] The invention further comprises the use of any of the abovedescribed processes for the preparation of5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-7-benzothiophenylmethyl]-2,4-thiazolidinedioneand5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedione-Na-salt.

[0068] A further embodiment of the present invention comprises thecompound5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedione-Na-salt.

[0069] The following examples shall illustrate preferred embodiments ofthe present invention but are not intended to limit the scope of theinvention.

EXAMPLE 1 1-(2-Thienyl)allyl Acetate

[0070] A 1.5 l 4-necked glass flask equipped with a mechanical stirrer,a thermometer and an argon inlet was charged with 112.2 g of2-thiophenecarbaldehyde (1.00 mol) and 100 ml of THF and to theresulting solution was added dropwise at −20° C. within 1.2 h 650 ml ofvinylmagnesium chloride 1.7 M solution in THF. The temperature duringthe addition was kept between −20 and −25° C. with aid of an acetone/dryice bath, then increased to 0° C. during 35 min and kept at thistemperature for 20 min. To the resulting brown suspension was added atca. 0° within 40 min 132.7 g of acetic anhydride (1.30 mol). The coolingbath was removed and after stirring for 1 h 400 ml of deionized waterwas added at 10-15° C. within 20 min. The biphasic yellow-brown mixturewas stirred for an additional 1 h at room temperature and transferred toa separatory funnel with aid of 500 ml of hexane. The brown aqueousphase was separated and extracted with 400 ml of hexane. The combinedorganic phases were washed with 3×200 ml deionized water, dried (Na₂SO₄,15 min stirring) and rotatory evaporated (T_(bath) 35°, 12 mbar, 1 h).Material of this quality is defined as “crude” and is also suitable forcyclocarbonylation (see Example 2 B). The orange-brown oil (199.7 g) wasdistilled in an apparatus consisting of a 500-ml two-neckedround-bottomed flask, a distillation head with water-cooling and afraction sampler. A forerun containing low-boiling components (yellowishoil) was collected at T_(head) between room temperature and 55° C. and0.5-0.6 mbar, the main fraction was collected at T_(head) of 59-62° C.(T_(pot) 63-67° C.) and 0.4 mbar.

[0071] Yield: 161.53 g (88.6%) of 1-(2-thienyl)allyl acetate as aslightly yellow oil.

EXAMPLE 2 A 4-Hydroxybenzothiophene

[0072] An autoclave was charged under an argon flow with 27.34 g of1-(2-thienyl)allyl acetate (0.150 mol, distilled), 28.4 ml of aceticanhydride (30.6 g, 0.30 mol), 42.0 ml of triethylamine (30.7 g, 0.30mol), 23.6 mg of palladium acetate (0.105 mmol) and 0.264 g oftriphenylphosphine (1.00 mmol), all with aid of 53 ml of toluene. Thenthe autoclave was sealed, evacuated twice under slow stirring (150 rpm)to 0.2 bar and pressurized with 8 bar of argon, then pressurized threetimes with 20 bar of carbon monoxide and vented, and finally pressurizedwith 50 bar of carbon monoxide. The reaction mixture was stirred (500rpm) and heated at 120° C. and the carbonylation carried out at 50 barconstant total pressure for 6 h. After cooling, the autoclave was ventedand the CO atmosphere was exchanged by evacuating to ca. 0.2 bar andpressurizing 8 bar of argon four times. The resulting dark solution waspoured into a 0.5 l flask containing 120 ml of ice water and thebiphasic solution was stirred for 1 h at room temperature. The aqueousphase was extracted in a separatory funnel with 80 ml of toluene andthan the combined organic phases were washed with 3×30 ml, with a totalof 90 ml of deionized water and reduced to a total weight of 46 g byrotary evaporation (50° C./60 mbar).

[0073] The residue containing the crude acetate was transferred to a0.35 l glass flask under argon with aid of 25 ml of toluene. Afteraddition of 82 ml of 4N sodium hydroxide (328 mmol) the mixture wasstirred intensively (1200 rpm) at 50° for 1.5 h and then after coolingtransferred in a 0.5 l separatory funnel. After removal of the organiclayer, the dark aqueous phase was extracted with 80 ml of toluene andthe combined organic phases were back-extracted with 2×20 ml, a total of40 ml of deionized water. The combined aqueous phases were treated with1.0 g of charcoal, stirred at room temperature for 5 min under argon andfiltered through a Speedex layer. The filter cake was rinsed three timeswith 20 ml, a total of 60 ml of deionized water. The clear brown,combined phases were concentrated until no more toluene distilled, thenafter cooling to 5° C. in an ice bath 75 ml of 25% HCl were added underargon during 35 min, whereas the temperature was kept under 150 with aidof an ice bath. The resulting thick crystalline suspension was stirredfor 1 h in an ice bath (internal temperature 2-3° C.) and filtered on asintered glass filter. The filter cake was washed three times with 50ml, a total of 150 ml of ice-cold water and dried on the rotavapor at50° C./1 mbar to constant weight.

[0074] Yield: 18.9 g (84%) of 4-hydroxybenzothiophene

[0075] m.p. 76-78° C., content: 98%.

EXAMPLE 2 B 4-Hydroxybenzothiophene

[0076] An autoclave was charged under an argon flow with 27.34 g of1-(2-thienyl)allyl acetate (0.150 mol, crude quality, see Example 1),28.4 ml of acetic anhydride (30.6 g, 0.30 mol), 42.0 ml of triethylamine(30.7 g, 30 mol), 23.6 mg of palladium acetate (0.105 mmol) and 0.264 gof triphenylphosphine (1.00 mmol), all with aid of 53 ml of toluene.Then the autoclave was sealed, evacuated twice under slow stirring (150rpm) to 0.2 bar and pressurized with 8 bar of argon, then pressurizedthree times with 20 bar of carbon monoxide and vented, and finallypressurized with 50 bar of carbon monoxide. The reaction mixture wasstirred (500 rpm) and heated at 120° C. and the carbonylation carriedout at 50 bar constant total pressure for 6 h. After cooling, theautoclave was vented and the CO atmosphere was exchanged by evacuatingto ca. 0.2 bar and pressurizing 8 bar of argon four times. The resultingdark solution was poured into a 0.5 l flask containing 120 ml of icewater and the biphasic solution was stirred for 1 h at room temperature.The aqueous phase was extracted in a separatory funnel with 80 ml oftoluene and then combined organic phases were washed with 3×30 ml, atotal of 90 ml of deionized water and reduced to a total weight of 46 gby rotary evaporation (50° C./60 mbar).

[0077] The residue containing the crude acetate was filtered through 17g of silica gel (Ø=3 cm) and the filter washed with 150 ml of toluene.The combined organic phases were reduced to a total weight of 40 g byrotary evaporation and transferred to a 0.35 l glass flask under argonwith aid of 20 ml of toluene. After addition of 82 ml of 4N sodiumhydroxide (328 mmol) the mixture was stirred intensively (1200 rpm) at50° for 1.5 h and then after cooling transferred in a 0.5 l separatoryfunnel. After removal of the organic layer, the dark aqueous phase wasextracted with 80 mol of toluene and the combined organic phases wereback-extracted with 2×20 ml, a total of 40 ml of deionized water. Thecombined aqueous phases were treated with 1.0 g of charcoal, stirred atroom temperature for 5 min under argon and filtered through a Speedexlayer. The filter cake was rinsed three times with 20 ml, a total of 60ml of deionized water. The clear brown, combined phases wereconcentrated until no more toluene distilled, then after cooling to 5°C. in an ice bath 75 ml of 25% HCl were added under argon during 35 min,whereas the temperature was kept under 15° with aid of an ice bath. Theresulting thick crystalline suspension was stirred for 1 h in an icebath (internal temperature 2-3° C.) and filtered on a sintered glassfilter. The filter cake was washed three times with 50 ml, a total of150 ml of ice cold water and dried on the rotavapor at 50° C./1 mbar toconstant weight. Yield: 16.5 g (73%) of 4-hydroxybenzothiophene as browncrystals-

[0078] m.p. 75-76° C., content: 95%.

EXAMPLE 3 Variation of Phosphorus Ligands

[0079] 4.93 mg of palladium acetate and 57.57 mg of triphenylphosphinein 10 ml of toluene were stirred for 1 h in a glove-box (O₂<1 ppm). A 35ml autoclave was charged with 0.40 g of distilled 1-(2-thienyl)allylacetate, 0.42 ml of acetanhydride, 0.62 ml of triethylamine and 1.0 mlof the catalyst solution described above. The autoclave was conditionedwith 30 bar of CO and pressurized with 70 bar of CO. Thecyclocarbonylation was carried out at 120° C. for 2 h. GC-analysisrevealed a conversion of 96% with a content of 4-acetoxybenzthiophene of91%.

[0080] A) Examples 3.1-3.6:

[0081] According to Example 3, table 1 summarizes the followingexperiments which were performed with phosphorus ligands other thentriphenylphosphine. TABLE 1 % con- % Content of Example P-ligand^(b))version^(a)) 4-Acetoxybenzothiophene^(a)) 3.1 PPh(3,5-tBu-Ph)₂ 92 87 3.2P(3,5-tBu-Ph)₃ 93 88 3.3 AMPHOS 99 95 3.4 NMDPP 98 94 3.5 P(2-Puryl)₃ 9690 3.6 P(o-DMA-Ph)₃ ^(c)) 13 12

[0082] B) Examples 3.7-3.23:

[0083] The following additional examples 3.7 to 3.23 were performed withfurther phosphorus ligands. The reaction were performed according to thedescription given above. However, the autoclave was pressurized with 50bar CO and the cyclocarbonylation reaction was carried out at 90° C. for16-18 h. TABLE 2 Example % con- No. P-Ligand^(b)) P/Pd^(c)) version^(a))% Content^(a)) 3.7 PPh(3,5-tBu-Ph)₂ 2 >99 94 3.8 P(3,5-tBu-Ph)₃ 2 >99 973.9 PAMP 2 >99 92 3.10 MOP 2 >99 92 3.11 P(2-Furyl)₃ 10 >99 85 3.12TROPP-Ph 6 >99 95 3.13 PPh(Diphol) 6 >99 88 3.14 (S,S)-DDPPI 2 >99 923.15 DPEphos 2 99 40 3.16 DPPM 2 40 30 3.17 DIOP 4 99 72 3.18P(O-nC₄H₉)₃ 6 99 86 3.19 Diphol-DIOP 2 99 71 3.20 DPPF 2 >99 81 3.21TPP-ox-Ph 1 85 44 3.22 P(m-Tol)₃ 6 >99 83 3.23 P(n-Bu)₃ 6 95 70

EXAMPLE 4 Cyclocarbonylation Reactions: CO Pressure and S/Pd Ratio

[0084] 6.0 g of distilled 1-(2-thienyl)allyl acetate were reacted for 4h as described in Example 2 A with 6.2 mg of palladium acetate, 72.1 mgof triphenylphosphine, 6.3 ml of acetanhydride and 9.3 ml oftriethylamine present. GC-analysis revealed a conversion of 98% with acontent of e-acetoxybenzthiophene of 94%.

[0085] Examples 4.1-4.7:

[0086] According to Example 4 table 2 summarizes experiments performedunder different reaction conditions (CO pressure and S/Pd ratio). TABLE2 Example % yield^(b)) No. P_(CO) [bar]^(a)) S/Pd T [° C.] 2 h 4 h 6 h4.1 70 1200 120 99 — — 4.2 70 ″ 100 90 98 n.d. 4.3 40 ″ 120 96 99 >994.4 20 ″ ″ 67 88 89 4.5 70 1500 ″ 97 >99 — 4.6 50 ″ ″ n.d. n.d. >99 4.740 ″ ″ 92 97 98

EXAMPLE 5 4-[2-(Benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole

[0087] 218 g (1.45 mol) of 4-hydroxy-benzothiophene and 511 g (1.82 mol)of mesylate of Formula V

[0088] were dissolved in 5.41 of DMF, followed by addition of 555 g(4,02 mol) of potassium carbonate (dry). The reaction mixture wasstirred at 100 to 105° C. for 6 to 8 hours. The resulting suspension wascooled to 5° C. and 7 l of water was added. The suspension was stirredat 5° C. for 30 minutes. The precipitate was filtered with suction andwashed with 550 ml of DMF/water (1:1) and 1,1 l water. The precipitatewas stirred at 0 to 5° C. in 11 of MEK (methylethylketone) for 30minutes. Then the precipitate was filtered with suction and dried at 50°C.

[0089] Yield: 365 g (=75%)4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole.

[0090] m.p.126° C./129-131° C.

EXAMPLE 65-Methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole

[0091] 286 g (0.853 mol) of4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole weresuspended in 6.3 l of glacial acetic acid. Temperature was raised to 60°C. The resulting Clear solution was cooled to 25° C. 132 ml (3.18 mol)of 100% nitric acid were added within 3 minutes. The reaction mixturewas cooled below 30° C. After crystallization the suspension was stirredat 18 to 20° C. for 1 hour. The precipitate was filtered with suctionand washed with 2×600 ml of tert-butyl methyl ether. The residue wassuspended in 4 l of acetic ester for 15 minutes. 200 g (1.9 mol) ofsodium carbonate in 3 l water were added. The resulting suspension wasstirred for 1 hour. Acetic ester was distilled off followed by additionof 2 l of water. The suspension was stirred for 30 minutes. Theprecipitate was filtered with suction, washed with water and dried (50°C., 24 hours).

[0092] Yield: 210 g of5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole(=70%).

[0093] m.p. 149-151° C.

EXAMPLE 75-Methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole

[0094] 50 g (1.052 mol) of5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazolewere solved in 1 l of THF at 20 to 25° C. 75 ml Lewatit M 600 (OH⁻-form)(Bayer AG) were washed with about 100 ml THF, added to the5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazolesolution and stirred at room temperature for 1 hour. Then the Lewatit M600 material was filtered with suction and washed with 100 ml THF. 12.5g of Raney nickel were added to the combined THF solutions followed byhydrogenation of the5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleat standard pressure. The temperature of the reaction mixture should notexceed 35 to 40° C. Hydrogen pressure was increased to 6 bar within 6hours. After hydrogenation the reaction mixture was stirred for 1 hour.Then the catalyst was filtered with suction, the THF was distilled off,180 ml ethanol was added and the residue was boiled out for 30 minutes.The reaction mixture was stirred at 0° C. for 1 hour. The precipitatewas filtered with suction and the residue was washed with 25 ml ethanoland dried for 24 hours at 50° C. (vacuum).

[0095] Yield: 42.4 g of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole(=92%).

[0096] m.p. 122-126° C.

EXAMPLE 8Methyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate

[0097] 320 g (0.91 mol) of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazolewere solved in 6.41 acetone. Within 30 sec one third of a 320 ml (2.74mol) of 48% HBr in 900 ml water were added. After cooling to 0 to 4° C.and crystallization the suspension was stirred at 0 to 4° C. for 1 hour.Then the remaining 48% HBr solution in water was added within 15 minutesat 0 to 4° C. and stirred at this temperature for 15 minutes followed byaddition of 63.9 g (0.93 mol) sodium nitrite in 180 ml water within 15minutes at 3 to 5° C. and stirring for 30 minutes at 3 to 5° C. 1230 mlof methacrylate CH═CHCOOCH₃ (13.6 mol) was added to this reactionmixture at 10 to 14° C. followed by addition of 3.2 g Cu(I)bromide.Temperature was increased to 20 to 25° C. within 30 minutes followed bystirring at this temperature for 1 hour and 10 minutes at 30° C. 1.8 lof water was added to the reaction mixture followed by distillation ofacetone/methacrylate CH═CHCOOCH₃ at a temperature of 40° C. The finalvolume was about 21.1 l of water was added to separate the remainingmethacrylate CH═CHCOOCH₃. The final volume was about 21. The blackprecipitate was solved by addition of 4.5 l of acetic ester and stirringfor 15 minutes. The two phase reaction mixture was filtered and theaqueous phase was extracted with 2 l of acetic ester. After extractionwith 2 l of an aqueous 2% NaCl-solution the acetic ester solutions werecombined and distilled. 2 l of acetic ester was added to the residue andagain distilled. 3 l of ethanol were added to the residue and boiled. 15g of activated charcoal were added and stirred for 15 minutes. Afterfiltration and cooling to room a precipitate was formed. The suspensionwas stirred for 1 hour at room temperature and an additional hour at 0°C. After washing with cold ethanol the precipitate was dried for 24hours at 50° C. (vacuum).

[0098] Yield: 310 g ofmethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate(=68%).

[0099] m.p. 97 to 99° C.

EXAMPLE 92-Imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one

[0100] 190 g (0.380 mol) of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazolewere suspended in 2.85 l of ethanol. 31.6 g (0.415 mol) of thiourea and34.8 g of sodium acetate were added. After boiling for about 18 hours(reflux) the reaction mixture was cooled to 0 to 4° C. and stirred for1.5 hours at this temperature. The precipitate was filtered with suctionand washed twice with 250 ml cold ethanol. 1.9 l of water was added tothe residue, the mixture was stirred for 10 minutes and the precipitatewas filtered with suction and dried for 24 hours at 80° C. (vacuum).

[0101] Yield: 147 g of2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one(84%);

[0102] m.p: 224-227° C.

EXAMPLE 105-[7-[2-(5-Methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedione

[0103] 283.3 g (0.61 mol) of2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-onewere suspended in 2.83 l ethanol. 2.83 l of 2 N hydrochloric acid wereadded. The resulting suspension was stirred for 18 hours (reflux). Thesuspension was cooled for 1 hour to 0 to 4° C. and was stirred foranother 2 hours at this temperature. The precipitate was filtered withsuction and washed twice with 285 ml of ethanol. 2.83 l of water wasadded to the residue, the suspension was stirred for 30 minutes, theprecipitate was filtered with suction and washed with 2 l of water. Theprecipitate was dried for 24 hours at 80° C. and then solved in 545 mlDMF (at 85 to 90° C.). 4.95 l of ethanol (25° C.) were added to thesolution. The resulting suspension was stirred for 2 hours at 0 to 4° C.The precipitate was filtered with suction, washed with 270 ml of coldethanol and dried at 80° C. for 24 hours (vacuum).

[0104] Yield: 246 g of5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedione(87%);

[0105] MP: 224-227° C.

EXAMPLE 115-[7-[2-(5-Methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedione-Na-salt

[0106] (5-{7-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-ylmethyl}-2,4-thiazolidinedione) (5.8 g) wasdissolved in hot THF (87 ml). A solution of sodium hydroxide (0.5 g) inwater (6 ml) was added, and the solution was cooled to room temperature.Another portion (87 ml) of THF was given to the solution, and after ashort time a crystallization was observed. 150 ml of the solvent wasdistilled off in the heat. The suspension was cooled to about 0° C. andwas stirred for further 2 hours. The solid was filtered and dried at 80°C.

[0107] Yield: 5.6 g of5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedione-Na-salt(93%);

[0108] MP:>300° C. (decomposition).

What is claimed is:
 1. A process for the preparation of bicycliccompound of the formula

comprising cyclocarbonylating a monocyclic compound of the formula

wherein Y is halogen or —OR; and —OR is an aryloxy group or a group offormulae —O—(CO)—R′, —O—(CO)—O—R″ or —O—(PO)—(OR″)₂, wherein R′ isalkyl, perfluoro-C₁₋₂₀-alkyl, aryl, R″ is alkyl, aryl or benzyl; byreacting, in an organic solvent medium containing a base and acarboxylic acid anhydride, said monocyclic compound with carbon monoxidein the presence of a carbonylation catalyst capable of complexing withcarbon monoxide, said cyclocarbonylation reaction being carried out byintroducing carbon monoxide gas into the reaction medium to form thecarboxylic acid ester of the compound of formula I and thereaftersaponifying said ester formed by said carbonylation reaction by treatingsaid ester product in said reaction medium with a base at a pH of from 8to 14 to form said bicyclic compound.
 2. The process of claim 1, whereinsaid cyclocarbonylation reaction is carried out in the presence of abase and a catalyst which is a complex of a transition metal compoundwith a ligand.
 3. The process of claim 2, wherein the transition metalcompound is a palladium salt or a palladium on an inert support.
 4. Theprocess of claim 3, wherein the transition metal compound is selectedfrom a group consisting of Pd(OAc)₂, Pd₂dba₃, PdCl₂, Pd₂Cl₂(x-allyl)₂,PdCl₂(NCMe)₂, [Pd(NCMe)₄](BF₄)₂ or Pd/C.
 5. The process of claim 4,wherein the palladium compound is Pd(OAc)₂.
 6. The process of claim 3,wherein the ligand is P(R¹)(R²)(R³) or (R¹)(R²)P—(X)—P(R¹)(R²) whereinR¹, R² and R³ each independently are C₁₋₈-alkyl, cyclohexyl, benzyl,naphthyl, 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thiophenyl, 2- or 3-or 4-pyridyl, phenyl or phenyl which is substituted by C₁₋₄-alkyl,C₁₋₄-alkoxy, halogen, trifluoromethyl, lower alkylydenedioxy or phenyland X is binaphthyl, 6,6′-dimethyl- or 6,6′-dimethoxybiphenyl-2,2′-diyl,or one of the groups —(CH₂)_(n)—, —CH₂ CH₂—P(C₆H₅)—CH₂CH₂—,

and n is a number from 1 to
 8. 7. The process of claim 6, wherein theligand is selected from a group consisting of triphenylphosphine, and


8. The process of claim 7, wherein the ligand is triphenylphosphine,


9. The process of claim 3 or 7, wherein the cyclocarbonylation reactionis carried out in the presence of a base selected from the groupconsisting of tri-alkyl-amines, di-alkyl-aryl-amines, pyridines,alkyl-N-piperidines, sodium hydroxide, potassium hydroxide or salts ofcarbonic acids.
 10. The process of claim 3 or 7, wherein thecyclocarbonylation reaction is carried out in the presence oftriethylamine.
 11. The process of claim 3 or 7, wherein thesaponification reaction is carried out in a biphasic mixture of sodiumhydroxide in toluene or in a homogeneous mixture of sodium methylate inmethanol.
 12. A process for the preparation of a compound of formula II

wherein Y is halogen or —OR; and —OR is an aryloxy group or a group offormulae —O—(CO)—R′, —O—(CO)—O—R″ or —O—(PO)—(OR″)₂, wherein R′ isalkyl, perfluoro-C₁₋₂₀-alkyl, aryl, R″ is alkyl, aryl or benzyl;comprising reacting a thiophene carbaldehyde of formula

with a reagent of the formula vinyl-metal-X wherein -metal-X is —MgCl,—MgBr, —MgI or —Li, followed by reaction with an acid derivativeselected from a group consisting of (R′—CO)₂O, R″O—(CO)—Cl,Cl—(PO)(OR″)₂ or R″—(CO)—Hal, wherein R′ is alkyl,perfluoro-C₁₋₂₀-alkyl, aryl, R″ is alkyl, aryl or benzyl and Hal is Clor Br to form said compound II.
 13. The process of claim 12, wherein theacid derivative is acetanhydride.
 14. The process of claim 13, whereinthe vinyl-metal-X-reagent is vinylmagnesium chloride.
 15. The process ofclaim 14, wherein the compound of Formula II is prepared by reaction ofthe thiophene carbaldehyde by reaction of vinylmagnesium chloridefollowed by reaction with acetanhydride.
 16. The process of claim 14,wherein the compound of Formula I is 4-hydroxybenzothiophene.
 17. Theprocess of producing the product4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole byreacting a compound of formula I

with a mesylate of formula V

under basic conditions to form said product.
 18. The process of claim17, wherein4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole isconverted into5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleby nitration.
 19. The process according to claim 18, wherein5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleis converted into of 5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole by hydrogenation.
 20. The processaccording to claim 19, wherein 5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole is converted intomethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate byreaction with HHal/NaNO₂ followed by reaction with CH═CHCOOCH₃/Cu(I)Hal,wherein Hal is Br or Cl.
 21. The process according to claim 20, whereinmethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionateis converted into2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-oneby reaction with thiourea.
 22. The process according to claim 21,wherein2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-oneis converted into5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedioneby reaction under acid conditions.
 23. The process of claim 21, wherein5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedioneis converted into5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedione-Na-saltby reaction under basic conditions.
 24. The process for preparing5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedionecomprising a) conversion of a compound of the formula I

 into 4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole byreaction of a compound of formula I with a mesylate of formula V

 under basic conditions; followed by b) nitration of4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole to give5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole;c) hydrogenation of5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleto give5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole;followed by d) reaction of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazolewith HHal/NaNO₂ and CH═CHCOOCH₃/Cu(I)Hal, wherein Hal is Br or Cl togivemethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate;followed by e) reaction ofmethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionatewith thiourea to give2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one;followed by f) reaction of2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-oneunder acid conditions to give5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedione;and g) optionally followed by reaction of5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinoneunder basic conditions to give5-[7-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedione-Na-salt.25. The compound comprising5-[7-[2-(5-Methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-4-methyl]-2,4-thiazolidinedione-Na-salt.